ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.46A>T (p.Met16Leu)

gnomAD frequency: 0.00003  dbSNP: rs1390412870
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000630906 SCV000751879 uncertain significance Fanconi anemia 2023-10-13 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 16 of the FANCC protein (p.Met16Leu). This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with FANCC-related conditions. ClinVar contains an entry for this variant (Variation ID: 526382). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FANCC protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000630906 SCV002012444 uncertain significance Fanconi anemia 2021-10-28 criteria provided, single submitter clinical testing The FANCC c.46A>T (p.Met16Leu) missense change has a maximum subpopulation frequency of 0.0016% in gnomAD v2.1.1 (PM2_supporting; https://gnomad.broadinstitute.org/variant/9-98011528-T-A?dataset=gnomad_r2_1). Six of six in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional assays. To our knowledge, this variant has not been reported in individuals with Fanconi anemia. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_supporting, BP4.
Ambry Genetics RCV003162794 SCV003878550 likely benign Hereditary cancer-predisposing syndrome 2022-12-13 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx RCV003238790 SCV003936676 uncertain significance not provided 2022-12-29 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Natera, Inc. RCV000630906 SCV002081315 uncertain significance Fanconi anemia 2018-08-24 no assertion criteria provided clinical testing

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